Hantaviruses are spread from infected rodents to man in dust particles derived from rodent urine, feces or saliva. Old World hantaviruses were first recognized during the Korean war, infecting thousands of U.S. troops with 10% mortality. These viruses currently are estimated to cause 50,000-200,000 deaths each year in Asia. New World hantaviruses include the Sin Nombre virus that caused an outbreak in the southwestern U.S. in 1993 and Andes virus which has caused several severe epidemics in South America. New World hantaviruses cause hantavirus pulmonary syndrome (HPS) and are associated with severe clinical symptoms and up to 50% mortality. There are no drugs or therapies for hantavirus disease, or safe, effective vaccines. A vaccine is urgently needed in order to protect people in rural areas of the North and South America and Asia. Moreover, a hantavirus vaccine is very important to protect against potential bioterrorist attacks or military use. Hantaviruses are extremely stable, when dried in mouse urine in the wild, and without sophisticated stabilizing agents. These viruses can remain infectious for weeks. The viruses enter the human respiratory tract and cause lethal disease in young, healthy adults. Therefore, there is substantial potential for hantaviruses to be used in bioterrorism or biowarfare. We propose to construct non-replicating adenovirus (Ad) vectors expressing hantavirus proteins. Ad vectors are well established vaccine candidates in several areas including HIV, rabies and in cancer; and have major advantages over other vaccine strategies. Ad vectors do not replicate and spread to other hosts or cause disease as with other virus vectors such as vaccinia virus. Moreover, they produce robust cell-mediated immunity, a property which we hypothesize will be important in a vaccine that produces sustained, protective immunity. We will test several potential Ad-hantavirus vaccines in a recently described Syrian golden hamster model of hantavirus infection. The quality and quantity of CD8+, CD4+ T lymphocyte responses and NK cell responses will be evaluated. These studies will optimize the vaccine construct, delivery methods and production of immunity in hamsters. This will be a prelude to challenge experiments in which vaccinated hamsters will be challenged with Andes virus that causes a lethal pulmonary disease similar to that in humans. [unreadable] [unreadable]